Gene Is Linked to Susceptibility to Depression

By MARY DUENWALD

Published: July 18, 2003

Scientists have identified a gene that may help explain why some people become depressed in response to the stresses of life and others skate by relatively unscathed.

The gene, which comes in two forms, or alleles, can either protect people from depression or make them more vulnerable, researchers report today in the journal Science.

In the study, people who experienced job loss, death in the family, abuse or other traumas were much more likely to develop depression if they possessed two copies of the short allele. Those with two copies of the long allele (pronounced uh-LEEL) were able to withstand such events without becoming depressed.

''No matter how many stressful events they had in a five-year period, they were no more likely to become depressed than people who had no stressful events at all,'' said Dr. Terrie E. Moffitt, a psychologist at the University of Wisconsin and King's College London, who collaborated on the study with scientists in Britain and New Zealand.

People who have inherited the short allele from one parent and the long one from the other, the researchers found, are moderately vulnerable to depression.

The results tie together two of the greatest risk factors for depression.

''The evidence that stressful life events increase the risk of depression has been strong for about a decade,'' said Dr. Kenneth Kendler, a psychiatrist at Virginia Commonwealth University, in Richmond, who was not connected to the study.

''We also know that depression has a moderate level of heritability -- about half your risk of depression comes from your genes,'' he said. ''The question has been, do these risk factors add or do they multiply? The answer is that they multiply.''

The new findings also help explain the sharp differences in the way individuals react to stress.

''Almost all of us know people who are fairly stress free,'' Dr. Kendler said. ''They like to sky-dive. Or they work as emergency-room physicians. With others, when the boss gives them a bad evaluation, they're upset for a week.''

The study followed 847 New Zealanders from birth to age 26. Seventeen percent of the subjects carried two copies of the short allele, 31 percent had two copies of the long allele and 51 percent had one of each.

Over the years, the researchers tracked each subject's exposure to stressful events like long-term unemployment, debt problems, trouble in intimate relationships, homelessness, disabling injuries and physical or sexual abuse. Fifteen percent of the subjects suffered four or more such crises at ages 21 to 26.

Within that group, 43 percent of those with two copies of the short allele developed depression. Thirty-three percent of those with one short and one long allele did. But only 17 percent of those with two copies of the long gene developed depression, about the same number as would be expected to have depression had they experienced no crises at all.

Nearly twice as many women as men suffer from depression. Yet women were found no more likely than men to carry the short allele.

Perhaps, Dr. Moffitt said, women's vulnerability to depression is not connected to the way they respond to stressful events.

''There's nothing about this gene interacting with stress that accounts for the sex difference,'' Dr. Moffitt said.

Among those who suffered the most stressful events, the subjects with the short alleles were also more likely to consider or attempt suicide. Only 4 percent of those with the long alleles thought of killing themselves, compared with 11 percent of those with the short ones.

The long alleles also seemed to shield those who experienced abuse during childhood -- one subject in 10 -- from depression in adulthood, the researchers found.

The gene, known as 5-HTT, has been a focus of depression studies because it contains the code to produce a protein that escorts the chemical messenger serotonin across the spaces between brain cells, or synapses, and then clears away the leftover serotonin. Drugs like Prozac, Paxil, Zoloft and Celexa, which are widely effective in treating depression, work by acting on the serotonin system.

Earlier studies in mice and monkeys have shown a connection between the 5-HTT gene and anxiety. Last year, researchers at the National Institute of Mental Health found that people with two copies of the short allele were more likely than others to become anxious when shown pictures of scary faces.

The short allele produces the same protein as the long one, but less of it. As a result, Dr. Moffitt said, it manages serotonin less efficiently.

The study suggests that among people who suffer a series of stressful events, the gene could predict who will suffer depression about as well as a bone mineral density test can predict who will suffer a fractured hip, the researchers said.

Still, they said it was too early to use 5-HTT as a diagnostic test. The study must be repeated, and other genes that play a role in vulnerability to depression must identified.